Amygdala-ventral striatum circuit activation decreases long-term fear

Abstract

In humans, activation of the ventral striatum, a region associated with reward processing, is associated with the extinction of fear, a goal in the treatment of fear-related disorders. This evidence suggests that extinction of aversive memories engages reward-related circuits, but a causal relationship between activity in a reward circuit and fear extinction has not been demonstrated. Here, we identify a basolateral amygdala (BLA)-ventral striatum (NAc) pathway that is activated by extinction training. Enhanced recruitment of this circuit during extinction learning, either by pairing reward with fear extinction training or by optogenetic stimulation of this circuit during fear extinction, reduces the return of fear that normally follows extinction training. Our findings thus identify a specific BLA-NAc reward circuit that can regulate the persistence of fear extinction and point toward a potential therapeutic target for disorders in which the return of fear following extinction therapy is an obstacle to treatment.DOI: http://dx.doi.org/10.7554/eLife.12669.001

A Network Model of the Emotional Brain

“…Indeed, recent studies are now characterizing interactions between systems. For example, optical stimulation of a basolateral amygdala pathway to the accumbens facilitates reward seeking [48] and decreases long-term fear [49] (see also [50]). In sum, connectional systems communicate with each other at the level of the subcortical forebrain (Figure 2E), providing a substrate that affords greater integration and potential for context dependence.…”

Fear extinction requires infralimbic cortex projections to the basolateral amygdala

“…This includes ascertaining the BLA neuronal populations and interneuron cell types that are directly innervated by the IL, as well as certain cell populations that neighbor, are tightly coupled to the BLA and have been implicated in extinction, particularly the intercalated cell clusters (8,(31)(32)(33)(34)(35). In addition, recent data from Goosens and colleagues suggests that extinction can specifically recruit BLA-NAc circuits to suppress fear reinstatement (13). Moreover, optogenetic stimulation of BLA terminals in the NAc resulted in increased c-fos labeling in the IL, raising the possibility of an IL-BLA-NAc feedback circuit that promotes extinction.…”

“…Previous evidence from multiple lines of inquiry strongly implicates the medial prefrontal cortex (mPFC) in the mediation of extinction (1,(4)(5)(6), but the precise position of this region within the broader brain network underlying extinction remains incompletely understood. Recent studies in mice have shown that neuronal outputs from the ventromedial PFC (vmPFC), containing the infralimbic cortex (IL) region, to the basolateral (BLA) (7)(8)(9) and basomedial (BMA) (10), as well as reciprocal connections from BLA to IL (11,12) and projections from BLA to NAc (13) are important for extinction.…”

The nucleus accumbens core is necessary to scale fear to degree of threat

“…We identified the nucleus accumbens core (NAcc) as a likely candidate, based on its ability to rapidly process reward-predictive cues (Cromwell and Schultz, 2003;Setlow et al, 2003;Ambroggi et al, 2011;McGinty et al, 2013;Saddoris and Carelli, 2014;Sugam et al, 2014;Ottenheimer et al, 2018), as well as its anatomical connectivity with the amygdala (Kita and Kitai, 1990;Petrovich et al, 1996;Wright and Groenewegen, 1996). Even more, the NAcc is implicated in a variety of fear-related processes (Haralambous and Westbrook, 1999;Thomas et al, 2002;Schwienbacher et al, 2004;Iordanova et al, 2006a;Fadok et al, 2010;Badrinarayan et al, 2012;Oleson et al, 2012;Li and McNally, 2015;Correia et al, 2016).…”